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ORIGINAL PAPER
Social/economic costs and health-related quality of life in patientswith epidermolysis bullosa in Europe
Aris Angelis1• Panos Kanavos1
• Julio Lopez-Bastida2,3• Renata Linertova3,4
•
Juan Oliva-Moreno3,5• Pedro Serrano-Aguilar3,6
• Manuel Posada-de-la-Paz7•
Domenica Taruscio8• Arrigo Schieppati9 • Georgi Iskrov10,11
• Valentin Brodszky12•
Johann Matthias Graf von der Schulenburg13• Karine Chevreul14,15,16
•
Ulf Persson17• Giovanni Fattore18
• BURQOL-RD Research Network
Received: 4 May 2015 / Accepted: 13 January 2016 / Published online: 23 April 2016
� The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract
Background The aim of this study was to determine the
social/economic costs and health-related quality of life
(HRQOL) of patients with epidermolysis bullosa (EB) in
eight EU member states.
Methods We conducted a cross-sectional study of
patients with EB from Bulgaria, France, Germany, Hun-
gary, Italy, Spain, Sweden and the United Kingdom. Data
on demographic characteristics, health resource utilisation,
informal care, labour productivity losses, and HRQOL
were collected from the questionnaires completed by
patients or their caregivers. HRQOL was measured with
the EuroQol 5-domain (EQ-5D) questionnaire.
Results A total of 204 patients completed the question-
naire. Average annual costs varied from country to country,
and ranged from €9509 to €49,233 (reference year 2012).
Estimated direct healthcare costs ranged from €419 to
€10,688; direct non-healthcare costs ranged from €7449 to
€37,451 and labour productivity losses ranged from €0 to
€7259. The average annual cost per patient across all
countries was estimated at €31,390, out of which €5646
accounted for direct health costs (18.0 %), €23,483
accounted for direct non-healthcare costs (74.8 %), and
€2261 accounted for indirect costs (7.2 %). Costs were
Members of the BURQOL-RD Research Network listed in Annex I of
the ESM.
Electronic supplementary material The online version of thisarticle (doi:10.1007/s10198-016-0783-4) contains supplementarymaterial, which is available to authorized users.
& Aris Angelis
1 Department of Social Policy and LSE Health, London School
of Economics and Political Science, London, UK
2 University of Castilla-La Mancha, Talavera de la Reina,
Toledo, Spain
3 Red de Investigacion en Servicios Sanitarios en
Enfermedades Cronicas (REDISSEC), Madrid, Spain
4 Fundacion Canaria de Investigacion Sanitaria (FUNCANIS),
Las Palmas de Gran Canaria, Spain
5 University of Castilla-La Mancha, Toledo, Spain
6 Evaluation and Planning Service at Canary Islands Health
Service, Santa Cruz de Tenerife, Spain
7 Institute of Rare Diseases Research, ISCIII, SpainRDR and
CIBERER, Madrid, Spain
8 National Center for Rare Diseases, Istituto superiore di sanita
(ISS), Rome, Italy
9 Centro di Ricerche Cliniche per Malattie Rare Aldo e Cele
Dacco, Istituto di Ricerche Farmacologiche Mario Negri,
Ranica (Bergamo), Italy
10 Institute of Rare Diseases, Plovdiv, Bulgaria
11 Department of Social Medicine and Public Health, Faculty of
Public Health, Medical University of Plovdiv, Plovdiv,
Bulgaria
12 Department of Health Economics, Corvinus University of
Budapest, Budapest, Hungary
13 Centre for Health Economics Research Hannover (CHERH),
Leibniz Universitat Hannover, Hannover, Germany
14 URC Eco Ile de France, AP-HP, Paris, France
15 Universite Paris Diderot, Sorbonne Paris Cite, ECEVE,
UMRS 1123, Paris, France
16 INSERM, ECEVE, U1123, Paris, France
17 The Swedish Institute for Health Economics, Lund, Sweden
18 Centre for Research on Health and Social Care Management
(CERGAS), Bocconi University, Milan, Italy
123
Eur J Health Econ (2016) 17 (Suppl 1):S31–S42
DOI 10.1007/s10198-016-0783-4
shown to vary across patients with different disability but
also between children and adults. The mean EQ-5D score
for adult EB patients was estimated at between 0.49 and
0.71 and the mean EQ-5D visual analogue scale score was
estimated at between 62 and 77.
Conclusion In addition to its negative impact on patient
HRQOL, our study indicates the substantial social/eco-
nomic burden of EB in Europe, attributable mostly to high
direct non-healthcare costs.
Keywords Epidermolysis bullosa � Cost-of-illness �Social cost � Health-related quality of life � European
Union � Rare disease
JEL Classification I1
Introduction
Epidermolysis bullosa (EB) is a family of rare genetic der-
matological conditions. It consists of a group of inherited
connective tissue disorders characterised by the absence of a
particular cohesion protein in the skin that results in the
defective connection of its outer and inner layers (epidermis
and dermis) making it fragile [1, 2]. The result is that the top
layer of skin does not ‘stick’ securely to the layer beneath it,
and, where the two layers separate, a blister develops. EB can
be classified into four main types based on the layer of the
skin affected: EB simplex (EBS), junctional EB (JEB),
dystrophic EB (DEB), and the recently added Kindler syn-
drome (KS) [1, 3, 4]. Each type can be further subdivided at
the molecular level according to the structural gene targeted
by the mutation, but also at tissue level, either as generalised
(with sites of blistering corresponding to areas where friction
is caused by clothing) or localised (where blistering is
localised to the hands and feet) [1]. Depending on the
severity of the disease, which can vary from benign to life-
threatening, symptoms can include skin fragility, blistering
of the skin following mild friction or trauma, and blistering
of the mucous membranes or internal organs, often leading to
a shorter lifespan [3, 5–7]. The prevalence of EB is 5:100,000
live births, with no racial or gender differences [8]. In the EU,
the prevalence is estimated to be 2.4:100,000 population [9].
There is currently no cure for EB, and clinical man-
agement is focussed on treating the symptoms of the dis-
ease [2, 7]. Topical agents and dressings are typically used
for the treatment of skin lesions [10], and appropriate
follow-up is essential to monitor the patient for a multitude
of secondary psychological symptoms, in particular
depression, anxiety and behavioural disturbances [3].
The impact of the condition on patient health-related
quality of life (HRQOL) has been explored both from a
qualitative and a quantitative perspective [2, 3, 5–7, 11–15].
Qualitative results have revealed a high prevalence of
psychosocial problems and psychiatric symptoms [3, 13],
indicating the importance of providing the appropriate
psychological and peer support [2], in tandem with pain
management and nursing support, as part of a multidisci-
plinary approach [14]. More quantitative approaches have
assessed different HRQOL dimensions of EB patients
using a range of instruments including the dermatology life
quality index (DLQI) and the children’s dermatology life
quality index (CDLQI) [5], the QOLEB questionnaire [6,
15], the short form-36 (SF-36), Skindex-29, General Health
Questionnaire-12 (GHQ-12) and EuroQOL 5 dimensions
(EQ-5D) questionnaires [7], while others have also looked
at the burden to carers [7] and parents [12]. Overall, they
have shown impaired HRQOL for both the patients [5, 7,
11] and their carers [7, 12]. However, there is an absence of
economic and cost information related to the disease and its
impact. As part of the BURLQOL-RD initiative [16], this
study used patient-level primary data collected across eight
EU Member States (Bulgaria, France, Germany, Hungary,
Italy, Spain, Sweden and the UK) to estimate the social and
economic cost burden of EB in terms of direct healthcare,
direct non-healthcare, and loss of productivity (indirect)
costs, and also report the loss in HRQOL, for both patients
and their caregivers.
Methodology
Research design and sample
This was a bottom-up, cross-sectional, study of non-insti-
tutionalised patients diagnosed with EB who received
outpatient care. Because of the lack of patient registries at
national level, subjects were recruited with the assistance
of the EB associations across the study countries based on
the associations’ membership. The survey was anonymous
and the patients were contacted by their patient organisa-
tion. An EB diagnosis, non-institutionalised status and
membership with the respective EB national patient asso-
ciation were the criteria for patient eligibility. Question-
naire responses received by the research team had no
identification information (i.e. name, identification,
address/postcode, e-mail or telephone). All patients and
caregivers were informed about the study objective, data
confidentiality and were asked to indicate their under-
standing of the study conditions and agreement to partici-
pate. The study protocol was submitted to the London
School of Economics (LSE) Research Ethics Committee
and received an exemption.
Following identification of the patient sample, patient
associations administered questionnaires electronically or
by post to eligible patients between September 2011 and
S32 A. Angelis et al.
123
April 2013; however, the recruitment period did not exceed
6 months in any of the countries. The questionnaires were
distributed by e-mail and post through patient organisa-
tions. Demographic, clinical and resource use data were
collected from EB patients and their caregivers.
Costing methodology
We used the prevalence approach to estimate the resources
used and, subsequently, costs incurred from a societal
perspective. Disease prevalence takes into account all
direct healthcare resources used for prevention, treatment
and rehabilitation, other non-healthcare resources used
(formal and informal care), and lost labour productivity
within a given year (in a population or in a sample of
patients) as a consequence of the illness considered.
Prevalence-based cost-of-illness analysis has the advantage
of incorporating measurements of total annual healthcare
expenditure, which is particularly relevant for chronic
conditions requiring long-term treatment such as EB. In
this context, a bottom-up costing approach was used to
estimate total and average annual costs [17].
Data on resource utilisation were collected for each
patient and, where appropriate, for the caregiver as well.
To estimate resource utilisation, the questionnaire solicited
information regarding the 6-month period prior to the study
(12 months for hospital admissions), and extrapolated the
data to the entire year. We considered 6 months to be an
appropriate recall period. Productivity losses were calcu-
lated using data collected on reductions in patient and
caregiver working time (temporary and permanent sick
leave or early retirement). Non-professional caregivers
were also asked about informal care time.
Direct healthcare costs
Direct medical costs were derived from healthcare utili-
sation. The cost of resources used by patients was calcu-
lated based on the relevant unit costs and the average
utilisation per patient in the sample. Information about the
number of hospital admissions, the number of emergency
visits and data for the volume of outpatient care (rehabil-
itation, medical tests and examinations, visits to health
professionals and home medical care) were generated from
the questionnaires.
Unit costs were obtained from different databases used
in Europe on healthcare costs, and any remaining data gaps
were filled in using additional publicly available resources
(see Annex II of the ESM). To derive the annual cost per
patient, unit costs were multiplied by the respective
resource quantities, using 2012 as the reference year.
Similarly, resource utilisation information relating to use of
prescription drugs and medical support devices was
obtained from the questionnaires. When no information
concerning the number of units per pack was available, we
assumed the largest dispensing pack for prescription drugs.
Prescription drug unit costs were also obtained from gov-
ernment databases (see Annex II of the ESM), whereas unit
costs for medical support devices were obtained from
major electronic commerce websites.
Direct non-healthcare costs
Direct non-medical costs were quantified by aggregating
three items: non-healthcare transportation, social care ser-
vices (formal care), and caregiver’s time (informal care
provided by non-professional caregivers, who are often
relatives, but could also be friends or neighbours). Informal
care concerned the time spent helping the patient with their
basic activities of daily living (ADL), and the time spent
helping with necessary instrumental activities of daily
living (IADL) (recall method). As a conservative criterion,
and for preventing conjoint production, we have censored
the time of care to a maximum of 16 h per day (114 h per
week) when the time of care reported exceeded this figure.
To cost care hours, the proxy good method was used,
whereby time was valued as an output, and the care pro-
vided by the informal caregiver was valued such that if
they did not provide these services, they would have
instead been provided by a professional caregiver [18, 19].
Data on formal (paid) care provided by professional care-
givers and other social services were obtained from the
questionnaires and reported in the relevant category.
Productivity losses
Productivity losses were accounted for by converting
physical units (days of sick leave and early retirement) into
monetary units using the human capital approach [20].
Worker gross average earnings were used to proxy pro-
ductivity losses (see Annex II of the ESM). Therefore, our
calculations were based on average gross wage figures in
the Wage Structure Surveys by the National Statistics
Institutes of the participating countries. Annual labour
productivity losses were estimated for the year 2012.
Patient and caregiver outcomes
Patient and caregiver outcomes were obtained via the EQ-
5D [21], the Barthel index [22] and the Zarit burden
interview [23]. The EQ-5D is a generic instrument of
HRQOL commonly used in economic evaluations and
routinely included in health technology assessments
(HTAs). It has five dimensions (mobility, self-care,
everyday activities, pain/discomfort and anxiety/depres-
sion). The values and utilities are assigned a score on a
Social/economic costs and HRQOL in patients with EB in Europe S33
123
scale where 0 corresponds to death and 1 corresponds to
perfect health, with negative values being possible.
The second part of the EQ-5D consists of a vertical
20-cm, 0–100 visual analogue scale (VAS), where 0 rep-
resents the worst and 100 represents the best imaginable
health state. Respondents mark a point on the scale to
reflect their overall perception of health on the day of the
interview [21]. Evaluations of these health states have been
reported for the general population [24].
The Barthel index is widely used to assess physical
disability. It measures the ability of a person to perform ten
basic activities of daily living (ADL), and produces a
quantitative estimate of the subject’s degree of dependence
[22]. Total possible scores range either from 0 to 20 or
from 0 to 100, with lower scores indicating increased dis-
ability. All scores were converted into the 0–100 range. A
score of 91–99 shows mild dependence, 61–90 moderate
dependence, 21–60 severe dependence and\ 21 complete
dependence [25]. Following receipt of completed ques-
tionnaires, patients were grouped into two categories:
lower (i.e. no or mild) disability, defined as having a
Barthel index score between 91 and 100, and higher (i.e.
moderate, severe or complete) disability, for Barthel Index
scores lower than 91.
Lastly, the Zarit Burden Interview (22-item version)
measures the subjective burden among caregivers. Each
item is a statement that the caregiver is asked to respond to
using a five-point scale, with options ranging from 0
(never) to 4 (nearly always). The total score ranges from 0
to 88, where scores under 21 correspond to little or no
burden, and scores over 61 represent severe burden [23].
Results
A total of 339 questionnaires were collected in the eight
countries from people with EB, 135 of which were exclu-
ded because the information they contained was insuffi-
cient or inadequate. Therefore, the valid sample totalled
204 [8 Bulgaria, 37 France, 15 Germany, 6 Hungary, 35
Italy, 54 Spain, 6 Sweden and 43 United Kingdom (UK)].
The main characteristics of the sample are summarised
in Table 1. Of the total patient sample (n = 204), more
than half of participants were adults (n = 121), and their
average age was 26.7 years, with considerable uniformity
in the sample across countries in terms of average age, the
only outliers being Bulgaria, where patients were younger
(average 14.6 years) and the UK, where the patients were
older (average 34.3 years). Mean age for children in the
sample (n = 93) was 7.2 years. There was a higher
prevalence of female patients in the sample, accounting on
average for 59.8 % of respondents, with Hungary and
Sweden being outliers with an average of 33.3 and 83.3 %
males, respectively. Most patients, 60.3 % (n = 123), did
not require a caregiver.
The average age of caregivers, for those patients that
had one, was 40.3 years, and female caregivers dominated
the sample (86.4 %). Taking into account some missing
data, about half of the caregivers across the entire sample
were parents to the patients (53.1 %), followed by other
family relatives (23.5 %) and partners or others (12.3 %).
Across all countries, a substantial proportion of caregivers
was in paid employment other than caregiving (40.7 %),
with a considerable proportion being involved with
domestic activities (28.4 %) and a smaller proportion being
retired (11.1 %). The total average time spent caregiving
by the main caregiver (if there was at least one caregiver)
was estimated at between 34 h per week (France) and 90 h
per week (Bulgaria).
With regards to HRQOL, the mean EQ-5D index scores
(TTO tariff) ranged from 0.49 (Hungary) to 0.71 (Sweden)
(Table 2). The EQ-5D VAS scores ranged from 62 (Spain)
to 77 (Bulgaria) (Table 2). These scores are noticeably
lower than scores reported in the general population across
the study countries [24].
Over three-quarters of caregivers (n = 68) completed
the HRQOL portions of the questionnaire. Mean EQ-5D
index scores for caregivers ranged from 0.127 (Bulgaria) to
0.79 (Italy) (Table 2). Mean EQ-5D VAS scores for care-
givers (n = 66) ranged from 64.8 (Bulgaria) to 76.8 (Italy)
(Table 2).
The average Barthel index (BI) score of patients from
France and the United Kingdom reflected mild dependence
(96.9 and 91.9, respectively) (Table 2). The average BI
score of patients from Germany, Hungary, Italy, and Spain
reflected moderate dependence (85.8, 84.0, 73.3 and 81.4,
respectively). The average BI score of patients from
Sweden lay on the boundary between mild and moderate
dependence (90.8). The average BI score of patients from
Bulgaria reflected severe dependence (56.3). Lastly, the
average BI score across all countries reflected moderate
dependence (85.2).
The burden for caregivers was mild in the UK (average
Zarit scale score of 18.5) and moderate in France, Ger-
many, Italy and Spain (average Zarit scale scores of 35.3,
38.3, 31.6, 30.3, respectively) (Table 2). Across all coun-
tries, on average, the burden for caregivers was moderate
(Zarit scale score of 30.5). Average annual cost per patient
in 2012 was estimated at €17,671, €14,931, €46,116,
€9809, €49,233, €43,137, €9509, and €19,758, for patients
in Bulgaria, France, Germany, Hungary, Italy, Spain,
Sweden and the UK, respectively (Table 3). The largest
cost components were non-healthcare costs in all the
countries. Formal care had a minor weight in all countries
analysed except in Sweden. Meanwhile, informal care had
a major weight in Spain, the UK, France, Hungary,
S34 A. Angelis et al.
123
Ta
ble
1D
emo
gra
ph
icch
arac
teri
stic
so
fth
est
ud
yp
arti
cip
ants
(pat
ien
ts=
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4;
care
giv
ers=
81
)
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lgar
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ran
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ng
ary
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yS
pai
nS
wed
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nit
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do
mA
ver
age
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tien
ts
No
.8
37
15
63
55
46
43
Sex
,m
ales
(%)
37
.54
8.6
26
.76
6.7
48
.63
8.9
16
.73
2.6
40
.2
Av
erag
eag
ey
ears
(SD
)1
4.6
(19
.0)
27
.8(2
1.0
)2
8.6
(19
.1)
21
.3(1
8.9
)2
0.6
(15
.6)
25
.5(1
9.8
)2
7.0
(18
.3)
34
.3(1
9.9
)2
6.7
(19
.6)
Dis
ease
sub
typ
e(%
)a
Sim
ple
gen
eral
ised
0.0
40
.52
6.7
0.0
14
.31
8.5
16
.72
7.9
23
.0
Sim
ple
loca
lise
d0
.08
.12
6.7
0.0
2.9
9.3
50
.03
4.9
15
.2
Jun
ctio
nal
gen
eral
ised
37
.58
.16
.70
.08
.63
.70
.02
.36
.4
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ctio
nal
loca
lise
d0
.00
.01
3.3
0.0
0.0
0.0
0.0
0.0
1.0
Dy
stro
ph
icg
ener
alis
ed1
2.5
24
.32
6.7
66
.76
5.7
48
.10
.02
0.9
37
.3
Dy
stro
ph
iclo
cali
sed
25
.01
8.9
0.0
16
.78
.61
1.1
0.0
14
.01
2.3
Ca
reg
iver
s(m
ain
)
No
.5
96
22
32
61
9
Sex
,m
ales
(%)
0.0
0.0
16
.70
.02
1.7
15
.4n
/a1
1.1
13
.6
Av
erag
eag
e,y
ears
(SD
)3
5.4
(8.5
)4
1.6
(8.7
)4
0.0
(10
.8)
39
.0(5
.7)
36
.8(1
8.4
)4
7.7
(15
.3)
n/a
41
.5(1
4.0
)4
1.7
(15
.2)
Rel
atio
nsh
ipto
pat
ien
t(%
)b
Par
ent
n/a
55
.66
6.7
50
.02
1.7
92
.3n
/a4
4.4
53
.1
Oth
erre
lati
ve
n/a
11
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.00
.06
5.2
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n/a
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3.5
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tner
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/a1
1.1
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0.0
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n/a
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2.3
Em
plo
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us
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plo
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0.0
50
.04
7.8
42
.3n
/a3
3.3
40
.7
Ret
ired
n/a
0.0
0.0
0.0
13
.02
3.1
n/a
0.0
11
.1
Ho
use
wo
rker
n/a
22
.21
6.7
50
.02
1.7
34
.6n
/a5
5.6
28
.4
Oth
ern
/a1
1.1
33
.30
.01
3.0
3.8
n/a
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8.6
Av
erag
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edic
atio
n,
ho
urs
per
wee
k(S
D)d
89
.8(2
9.5
)3
4.3
(36
.7)
80
.3(3
7.0
)7
8.0
(48
.1)
59
.4(3
6.1
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0.8
(30
.7)
0.0
(n/a
)7
5.1
(50
.2)
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.4(3
8.8
)
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Social/economic costs and HRQOL in patients with EB in Europe S35
123
Ta
ble
2Q
ual
ity
of
life
char
acte
rist
ics
of
the
stu
dy
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tici
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ts
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lgar
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ind
exsc
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(0.2
79
)0
.60
6(0
.28
2)
0.7
07
(0.0
87
)0
.56
3(0
.34
0)
0.5
79
(0.2
80
)
Gen
eral
UK
po
pu
lati
on
(ad
ult
pat
ien
ts’
age-
adju
sted
),m
ean
(SD
)
0.8
5(0
.25
)0
.91
(0.1
6)
0.9
1(0
.16
)0
.91
(0.1
6)
0.9
3(0
.15
)0
.91
(0.1
6)
0.9
1(0
.16
)0
.91
(0.1
6)
0.9
1(0
.16
)
Mai
nca
reg
iver
sth
atco
mp
lete
dE
Q5
D
(n=
68
),m
ean
(SD
)a0
.12
7(0
.53
5)
0.7
34
(0.1
84
)0
.65
2(0
.41
2)
0.7
58
(0.0
15
)0
.78
6(0
.30
0)
0.7
38
(0.2
84
)n
/a0
.67
5(0
.17
0)
0.6
96
(0.3
34
)
Gen
eral
UK
po
pu
lati
on
(car
egiv
ers’
age-
adju
sted
),m
ean
(SD
)
0.9
1(0
.16
)0
.91
(0.1
6)
0.9
1(0
.16
)0
.91
(0.1
6)
0.9
1(0
.16
)0
.85
(0.2
5)
n/a
0.9
1(0
.16
)0
.91
(0.1
6)
VA
S
Ad
ult
pat
ien
tsth
atco
mp
lete
dV
AS
(n=
11
1),
mea
n(S
D)
77
.5(2
0.6
)6
8.7
(18
.3)
63
.2(2
1.8
)7
1.7
(10
.4)
63
.1(1
5.1
)6
2.4
(23
.1)
77
.5(2
0.6
)6
7.9
(23
.9)
66
.2(2
0.7
)
Gen
eral
UK
po
pu
lati
on
(ad
ult
pat
ien
ts’
age-
adju
sted
),m
ean
(SD
)
82
.0(1
8.2
)8
6.6
(13
.8)
86
.6(1
3.8
)8
6.6
(13
.8)
86
.6(1
3.8
)8
6.6
(13
.8)
86
.6(1
3.8
)8
6.6
(13
.8)
86
.6(1
3.8
)
Mai
nca
reg
iver
sth
atco
mp
lete
dV
AS
(n=
66
),m
ean
(SD
)b6
4.8
(17
.6)
67
.0(2
1.6
)6
6.3
(13
.8)
70
.0(2
8.3
)7
6.8
(14
.5)
75
.1(1
9.7
)n
/a6
9.2
(20
.4)
73
.1(1
8.0
)
Gen
eral
UK
po
pu
lati
on
(car
egiv
ers’
age-
adju
sted
),m
ean
(SD
)
86
.6(1
3.8
)8
6.6
(13
.8)
86
.6(1
3.8
)8
6.6
(13
.8)
86
.6(1
3.8
)8
2.0
(18
.2)
n/a
86
.6(1
3.8
)8
6.6
(13
.8)
Ad
ole
scen
tp
atie
nts
that
com
ple
ted
VA
S
(n=
41
),m
ean
(SD
)
70
.0(1
4.1
)5
9.3
(23
.9)
73
.8(2
2.9
)7
0.0
(28
.3)
51
.7(1
4.6
)6
9.0
(19
.1)
77
.5(2
4.7
)7
3.0
(22
.8)
65
.0(2
0.4
)
Za
rit
sca
le(n
56
8),
mea
n(S
D)c
n/a
35
.3(2
0.8
)3
8.3
(8.9
)n
/a3
1.6
(13
.9)
30
.3(1
1.7
n/a
18
.5(1
0.5
)3
0.5
(13
.7)
Ba
rth
elin
dex
(n=
14
9),
mea
n(S
D)d
56
.3(1
3.1
)9
6.9
(9.0
)8
5.8
(21
.0)
84
.0(1
6.4
)7
3.3
(26
.0)
81
.4(2
2.7
)9
0.8
(20
.1)
91
.9(1
4.7
)8
5.2
(21
.0)
SD
stan
dar
dd
evia
tio
n;VAS
vis
ual
anal
og
scal
ea
EQ
-5D
ind
exsc
ore
for
Sw
eden
’sm
ain
care
giv
ers
isn
ot
avai
lab
leb
ecau
seo
fm
issi
ng
dat
ap
oin
tb
VA
Ssc
ore
for
Sw
eden
’sm
ain
care
giv
ers
isn
ot
avai
lab
leb
ecau
seo
fm
issi
ng
dat
ap
oin
tc
Zar
itsc
ale
sco
res
for
Bu
lgar
ia,
Hu
ng
ary
and
Sw
eden
are
no
tav
aila
ble
bec
ause
of
mis
sin
gd
ata
po
ints
dB
arth
elsc
ore
sfo
rS
wed
enan
dU
Kw
ere
re-e
scal
ated
fro
ma
20
-po
int
scal
eto
a1
00
-po
int
scal
e
S36 A. Angelis et al.
123
Ta
ble
3A
ver
age
ann
ual
cost
sp
erp
atie
nt
(SD
),al
lp
atie
nts
(20
12
,€)
Bu
lgar
iaF
ran
ceG
erm
any
Hu
ng
ary
Ital
yS
pai
nS
wed
enU
KA
ver
age
Dru
gs
46
(78
)2
63
(13
10
)3
6(5
0)
48
(57
)2
79
4(1
66
4)
23
5(4
57
)3
(8)
50
(66
)6
06
(13
53
)
Med
ical
test
s5
0(6
6)
10
4(1
82
)1
87
(33
2)
25
(34
)9
5(2
47
)1
90
(31
6)
9(2
3)
19
7(4
61
)1
44
(31
2)
Med
ical
vis
its
27
1(2
95
)8
68
(14
90
)4
37
8(6
54
2)
74
(91
)1
82
5(1
84
4)
15
87
(38
37
)1
16
8(2
67
6)
19
45
(31
99
)1
67
0(3
30
1)
Ho
spit
aliz
atio
ns
99
0(2
28
2)
22
38
(73
35
)3
54
7(5
46
3)
21
8(4
78
)5
42
0(1
5,3
34
)2
04
2(6
19
7)
0(0
)4
01
(20
28
)2
26
7(8
06
0)
Hea
lth
mat
eria
l2
23
2(4
57
)1
37
1(1
70
1)
77
7(1
88
0)
44
(64
)5
49
(12
32
)3
90
(13
71
)2
98
(69
1)
15
32
(11
37
)9
24
(14
51
)
Hea
lth
care
tran
spo
rt0
(0)
10
(41
)1
53
(34
0)
10
(25
)4
(22
)6
6(4
23
)0
(0)
20
(93
)3
6(2
42
)
Dir
ect
hea
lth
care
cost
s3
58
9(2
60
4)
48
53
(98
06
)9
07
6(1
1,6
64
)4
19
(49
0)
10
,68
8(1
5,9
56
)4
51
1(8
58
4)
14
78
(33
87
)4
14
6(4
78
6)
56
46
(10
,06
2)
So
cial
hea
lth
serv
ice
25
6(5
90
)2
97
5(1
00
20
)2
24
3(7
32
2)
74
4(1
82
2)
18
96
(51
97
)5
98
(18
42
)2
29
0(5
60
9)
15
(98
)1
29
0(5
38
3)
Pro
fess
ion
alca
rer
0(0
)1
24
(55
6)
0(0
)0
(0)
40
3(1
66
1)
0(0
)5
08
8(1
2,4
63
)7
16
(46
94
)3
92
(31
07
)
No
n-h
ealt
hca
retr
ansp
ort
60
(14
9)
14
4(3
62
)1
56
(31
9)
10
9(2
11
)1
35
(41
5)
58
(11
4)
71
(17
4)
31
(76
)9
0(2
62
)
Mai
nin
form
alca
rer
86
30
(79
25
)4
34
6(1
1,9
13
)2
1,7
79
(31
,42
2)
65
29
(11
,46
6)
24
,22
7(3
1,3
00
)2
7,6
34
(32
,47
0)
0(0
)1
0,1
07
(24
,36
7)
16
,52
2(2
7,4
81
)
Oth
erin
form
alca
rers
48
70
(68
65
)1
29
4(5
12
2)
56
04
(12
,71
5)
20
09
(49
21
)1
0,7
90
(18
,88
8)
85
34
(18
,29
9)
0(0
)8
60
(40
87
)5
18
8(1
3,5
98
)
Dir
ect
no
n-h
ealt
hca
reco
sts
13
,81
7(1
3,5
44
)8
88
4(2
2,8
64
)2
9,7
81
(44
,83
4)
93
90
(16
,55
4)
37
,45
1(4
5,2
16
)3
6,8
24
(44
,97
4)
74
49
(18
,24
6)
11
,72
9(2
6,6
55
)2
3,4
83
(37
,93
8)
Pro
du
ctiv
ity
loss
26
5(7
50
)1
19
4(4
07
6)
53
(14
4)
0(0
)4
28
(21
89
)1
15
(71
8)
58
2(1
42
6)
83
(30
3)
36
9(2
03
6)
Ear
lyre
tire
men
t0
(0)
0(0
)7
20
6(1
4,9
19
)0
(0)
66
6(2
20
8)
16
88
(60
73
)0
(0)
38
00
(10
,60
0)
18
92
(72
92
)
Ind
irec
tto
tal
26
5(7
50
)1
19
4(4
07
6)
72
59
(14
,89
2)
0(0
)1
09
4(3
01
3)
18
03
(60
83
)5
82
(14
26
)3
88
4(1
0,5
74
)2
26
1(7
47
8)
TO
TA
L1
7,6
71
(14
,92
3)
14
,93
1(2
9,9
47
)4
6,1
16
(55
,97
6)
98
09
(16
,31
5)
49
,23
3(4
8,6
23
)4
3,1
37
(49
,86
4)
95
09
(21
,39
7)
19
,75
8(3
3,4
96
)3
1,3
90
(43
,57
7)
SD
stan
dar
dd
evia
tio
n
Social/economic costs and HRQOL in patients with EB in Europe S37
123
Bulgaria, Germany and Italy, with the exception being
Sweden, where informal care was virtually non-existent in
this sample of EB patients (Table 3). Loss of labour pro-
ductivity is a minor item in all countries with the exception
of Germany and the UK.
The average annual cost per patient across all countries
was estimated at a total of €31,390, out of which €5646
accounted for direct health costs (18.0 % of total), €23,483
accounted for direct non-healthcare costs (74.8 % of total),
and €2261 accounted for indirect costs (7.2 % of total)
(Fig. 1). Patients with no or mild disability (BI score
91–100) had a lower average annual cost of €6961 (direct
healthcare costs of €3170, direct non-healthcare costs of
€2396, indirect costs of €1394) whereas patients with
moderate or severe disability (BI score\ 91) had a higher
average annual cost of €48,491 (direct healthcare costs of
€7378, direct non-healthcare costs of €38,244, indirect
costs of €2868) (Fig. 2).
When looking specifically at the costs incurred by adults
(121 patients), data were included in the analysis based on
the sample sizes of all countries. Mean annual costs ranged
from €1003 per patient in Sweden to €35,857 in Italy
(Table 4). Direct healthcare costs ranged from €129 per
patient in Sweden to €11,025 in Italy. Direct non-health-
care costs ranged from €43 per patient in Bulgaria to
€22,816 in Italy. Loss of labour productivity costs ranged
from €0 per patient in Hungary to €12,098 in Germany
(Table 4).
For the paediatric patients, 83 were included in the
analysis based on the sample sizes of all countries. Mean
annual costs ranged from €5441 per patient in Hungary to
€68,181 in Germany (Table 5). Direct healthcare costs
ranged from €249 per patient in Hungary to €10,985 in
2% 1%
5%
7%3%
0%
4% 1%
0%
53%
17%
1%6%
Drugs
Tests
Visits
Hospitalisa�on
Material
Healthcare transport
Social-health services
Professional carer
Transport (non healthcare)
Main informal carer
Other informal carers
Pa�ent's produc�vity loss
Pa�ent's early re�rement
Fig. 1 Mean costs per average
epidermolysis bullosa (EB)
patient broken down by type of
cost (2012, €)
0
10,000
20,000
30,000
40,000
50,000
60,000
All pa�ents BI 91-100 BI <91
Indirect costs
Direct non-HC costs
Direct HC costs
Fig. 2 Direct healthcare (HC), direct non-healthcare (non-HC) and
indirect costs according to patient disability (2012, €)
S38 A. Angelis et al.
123
Germany. Direct non-healthcare costs ranged from €5192
per patient in Hungary to €59,236 in Spain (Table 5).
Discussion
Comparing HRQOL and economic burden across rare
diseases helps to inform priority setting for healthcare
resource allocation [4, 11, 15, 26]. Our study purports to be
the first of its kind to provide comprehensive information
on the costs of EB across several countries, and adds to the
existing literature on EB cost and HRQOL impact.
The average EQ-5D index score for adult patients with
EB was estimated at between 0.49 (Hungary) and 0.71
(Sweden). Patient HRQOL was not similar across the
countries, but consistently lower than general population
reference values.
Our results suggest that individuals living with EB have
markedly lower HRQOL than the general population and,
by extension, their caregivers also suffer decreased
HRQOL.
This analysis highlights the importance of studying the
economic consequences of EB and interpreting the results
in an international context. The results of our analysis
provide insights into the distribution of the costs of EB
and the impact of EB on national expenditures for
healthcare. We show that, in 2012, the estimated average
annual cost was €17,671, €14,931, €46,116, €9809,
€49,233, €43,137, €9509, and €19,758, for patients in
Bulgaria, France, Germany, Hungary, Italy, Spain, Swe-
den and the UK, respectively. The average annual cost
across all countries was estimated at €31,390 per patient,
with the highest proportion of costs being attributed to
direct non-healthcare (74.8 % of total), followed by direct
healthcare (18.0 % of total) and productivity loss (7.2 %).
Patients with a lower disease severity (as categorised
through their BI scores, 91–100) were associated with a
lower average cost of €6961 per patient, compared to
patients with a higher disease severity (BI score\ 91)
that were associated with a higher average cost of
€48,491.
The high costs of informal care underpin the social
economic burden of EB, accounting for more than half of
total costs. The clear divide and hidden social costs of EB
are relevant to policy-makers, especially when contem-
plating the impact across tiers of family income [7].
We found that EB had a consistent impact on the
HRQOL of patients and their caregivers regardless of the
country. In adults, direct healthcare costs, especially hos-
pitalisations, medical visits and health material, repre-
sented the vast majority of costs, while in children, medical
visits, hospitalisations and direct non-healthcare informal
costs, i.e. caregivers’ dedication time, were especially
predominant.
Table 4 Average annual costs per patient, adult patients (2012, €)
Spain
(n = 29)
UK
(n = 33)
France
(n = 22)
Bulgaria
(n = 2)
Hungary
(n = 3)
Germany
(n = 9)
Sweden
(n = 4)
Italy
(n = 19)
Drugs 239 40 53 93 73 25 5 3015
Medical tests 190 197 104 50 25 186 9 95
Medical visits 626 1689 437 465 32 4467 96 2289
Hospitalizations 1494 474 2037 63 396 2956 0 4642
Health material 559 1339 1126 2147 42 25 20 984
Healthcare transport 11 13 8 0 20 144 0 0
Direct healthcarecosts
3117 3752 3765 2817 589 7804 129 11,025
Professional carer 0 933 71 0 0 0 0 743
Non-healthcare
transport
45 19 75 5 196 88 0 211
Social services 897 19 2322 38 0 602 0 3478
Main informal carer 11,278 2442 778 0 9375 6069 0 12,052
Other informal carers 5282 0 403 0 4018 4745 0 6333
Direct non-healthcarecosts
17,502 3413 3649 43 13,589 11,504 0 22,816
Productivity loss 214 109 2008 1061 0 88 873 788
Early retirement 3143 4952 0 0 0 12,011 0 1227
Indirect costs 3357 5060 2008 1061 0 12,098 873 2016
TOTAL COSTS 23,976 12,226 9421 3921 14,178 31,406 1003 35,857
Social/economic costs and HRQOL in patients with EB in Europe S39
123
A recently published study analysing the socioeconomic
impact of ten rare diseases identified no available costing
studies of EB [27], apart from an old study that examined
the cost-effectiveness of the ‘‘Kozak protocol’’ in treating
nine children at a hospital in the Canadian province of
Ontario; however, due to a response indicating some seri-
ous data discrepancies, these costs were not studied in
depth [28, 29].
The only other quantitative study to quantify the
HRQOL burden of EB in the UK used the Dermatology
Life Quality Index (DLQI) in a Scottish population [5].
HRQOL loss due to EBS and DEB was observed to be
similar to severe psoriasis and atopic eczema [5], where
children ranked worse than adults. The DLQI was criticised
for underestimating the impact of more severe types of EB
by proposing questions on activities that may naturally be
incompatible with their daily lives (i.e. sports, gardening,
shopping) [4–6, 11, 26]. There are other qualitative studies,
however, that have investigated particular aspects of the
disease, such as the HRQOL impact of living with a gas-
tronomy tube [30, 31], living with wounds [14], dressings
and bandages [32] and their associated psychosocial impact
[2]. Elsewhere, worse median EQ-5D index scores were
reported for children than adults, and the occurrence of
problems with mobility, self-care, usual activities and pain/
discomfort was more common in children, with the
exception of anxiety/depression [7]. No significant
differences were observed in mean VAS scores between
children and adults, but the mean adult score of 62 (±23) is
comparable to our adult and adolescent scores of 66.2
(±20.7) and 65.0 (±20.4). By assessing changes in usual
activities, the EQ-5D questionnaire could also succumb to
the same flaws as the DLQI; consequently HRQOL values
presented in our study could be underestimates. More
concerned with levels of dependence in performing ADLs,
the Barthel index is less likely to be hindered by the
aforementioned methodological issue. Fine et al. [11] sur-
veyed ADL scores in a sample of children, albeit on a
different scale than the Barthel index, and observed that
most had partial dependence on a caregiver.
Administering both the SF-36 and the Skindex-29
(dermatology specific) questionnaires has been suggested
as the best option to evaluate HRQOL in EB patients,
striking an adequate balance between disease specificity,
conceptual validity, and comparability across diseases [4,
33]. Following this practice, one study noted that women
with EB had worse HRQOL compared to men [7], and a
second study classified individuals with JEB, RDEB and
DDEB as having some of the poorest HRQOL amongst
dermatological diseases; the milder EBS ranked close to
atopic dermatitis [15]. An EB specific quality of life
questionnaire (EBQOL) was developed and validated
across populations, although it does fail to fully quantify
psychological burden [6, 15].
Table 5 Average annual costs per patient, paediatric patients (2012, €)
Spain
(n = 25)
UK
(n = 10)
France
(n = 15)
Bulgaria
(n = 6)
Hungary
(n = 3)
Germany
(n = 6)
Sweden
(n = 2)
Italy
(n = 16)
Drugs 232 84 571 31 22 51 0 2532
Medical tests 190 197 104 50 25 186 9 95
Medical visits 2703 2790 1498 206 115 4243 3313 1275
Hospitalizations 2678 161 2532 1298 40 4433 0 6344
Health material 195 2169 1731 2261 47 1904 854 32
Healthcare transport 130 43 12 0 0 167 0 8
Direct healthcarecosts
6128 5443 6448 3846 249 10,985 4176 10,286
Professional carer 0 0 203 0 0 0 15,264 0
Non-healthcare
transport
73 71 246 79 22 257 213 45
Social services 251 0 3.933 329 1488 4704 6870 18
Main informal carer 46,606 35,400 9580 11,506 3683 45,343 0 38,685
Other informal carers 12,306 3698 2601 6494 0 6892 0 16,083
Direct non-healthcarecosts
59,236 39,169 16,563 18,408 5192 57,196 22,346 54,831
Productivity loss 0 0 0 0 0 0 0 0
Early retirement 0 0 0 0 0 0 0 0
Indirect costs 0 0 0 0 0 0 0 0
TOTAL COSTS 65,364 44,612 23,012 22,254 5441 68,181 26,522 65,117
S40 A. Angelis et al.
123
Qualitative studies have attempted to describe the
determinants of the lower HRQOL among patients with EB
and the wider social impact this disease may have on
patients and families alike, including the likely co-mor-
bidities that may emerge as a result. For children, the main
impediments were itchy skin, pain, limitations to partici-
pation in childhood activities (i.e. sports, outdoor activi-
ties), and the resulting social isolation [4, 5, 12]. Parental
and family support was crucial [3, 12], but caring for a
child was observed to adversely affect the parents’ mar-
riage and decrease their likelihood of having another child
[34]. The burden imposed on caregivers was related to the
severity of the condition [7, 34], and was affected by
perceptions of the child’s pain, the stigma associated with
being different, and limitations to family activities [12].
These factors are likely to have contributed to the lower
HRQOL scores reported by the caregivers in our sample.
As in children, the daily limitations on adult patients due
to pain and blisters were important [12], and the social
impact of EB was of significant concern [13]. Patients were
said to experience distress because of the life-long,
hereditary nature of the disease, as well as the social iso-
lation, discrimination and anxiety related to the visibility of
EB [2, 3, 13, 15]. In a study aiming to conduct a psy-
chosocial and psychiatric evaluation, 82 % of patients had
a deteriorated quality of life using the DLQI, and 80 % of
patients experienced psychiatric symptoms for which
severity was not related to EB [3].
Our study is not without limitations. We did not consider
EB type classification when calculating HRQOL and cost
burden. As such, even though disability status does capture
some of the variation in disease severity, conclusions drawn
from our subgroup analysis are restricted to broad compar-
isons unless the Barthel index scores of EB types are known.
In addition, attributing a general HRQOL detriment to EB is
complex due to the heterogeneity of severity across and
within categories [1, 2, 6]. The Birmingham Epidermolysis
Bullosa Severity (BEBS) score could have allowed for
stratification of patients based on disease severity to provide
more detailed cost estimates [10]. Though there are EB
(EBQoL) and dermatology-specific (Skindex-29) HRQOL
questionnaires, we used the EQ-5D as it has been deemed a
valid cross-sectional, generic measure of health outcomes in
rare diseases and is commonly used as the basis for economic
evaluations [7, 35]. However, it does appear pertinent to
argue for more accurate disease-specific tools and their wider
use in the future in terms of capturing some of the salient
features of individual diseases and the impact they may exert
on patients, which standard tools, such as the EQ-5D, may
not be able to capture [36]. A small sample size and
recruitment of solely patient volunteers could have intro-
duced a selection bias to the study, causing a preference for
patients with less severe illness, as they were more likely not
to be hospitalised and to be in contact with the association. If
this were true, we would have underestimated the economic
burden, as the high treatment costs related to hospitalisation
and long-term care could not have been considered. Fur-
thermore, recall biases are non-negligible when conducting
questionnaire-based studies and, like other HRQOL studies
on EB, cross-sectional data was used; restrictions as to the
scope and means of our study made the collection of longi-
tudinal data prohibitive, although this could have captured
patient adaptation to their diseased state [4].
The limitations of cost-of-illness studies outlined above
are generally trumped by their utility alongside population-
level data in helping to formulate health policies. By
adopting a bottom-up and annual approach for this study,
these first estimates of the costs of EB across eight EU
member states are likely to be complete and realistic.
Conclusion
The social/economic burden of EB, shared between the
high direct non-healthcare costs resulting from informal
care use and the loss of labour productivity, reinforce the
importance of not restricting cost analysis to direct
healthcare costs. Future public policy decisions and inter-
ventions for EB or other rare diseases, at a national and EU
level, should aim to take patient level cost disparities and
HRQOL effects into account.
Acknowledgments The authors wish to thank the following patient
organisations: National Alliance of People with Rare Diseases
(NAPRD), Bulgaria; Alliance Maladies Rares, France; ACHSE,
Germany; Hungarian Federation of People with Rare and Congenital
Diseases (RIROSZ), Hungary; Federazione Italiana Malattie Rare
(UNIAMO), Italy; the Consulta Nazionale delle Malattie Rare, Italy;
Rare Diseases Sweden; Federacion Espanola de Efermedades Raras
(FEDER), Spain; Rare Disease UK and Rare Diseases Europe
(EURORDIS); Debra Bulgaria; Debra France; Interessengemein-
schaft Epidermolysis Bullosa e.V., Germany; Epidermolysis Bullosa
Alapıtvany (DebRA Magyarorszag), Hungary; Debra Italia, Italy;
Debra Espana, Spain; Debra UK.
Compliance with ethical standards
Funding Supported by the social/economic burden and health-re-
lated quality of life in patients with rare diseases in Europe Project,
which has received funding from the European Union within the
framework of the Health Programme [Grant A101205]. The executive
agency of the European Union is not responsible for any use that may
be made of the information contained here.
Conflicts of interest The authors declare that they have no conflicts
of interest.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
Social/economic costs and HRQOL in patients with EB in Europe S41
123
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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